Bromoacetanilide carbamic acid esters useful as biocides

ABSTRACT

1. THE METHOD OF CONTROLLING THE GROWTH OF BACTERIA AND FUNGI COMPRISING APPLYING THEREOF AN EFFECTIVE AMOUNT OF A COMPOUND HAVING THE FORMULA   1-(R2-O-),3-(BR-CH2-CO-N(-R1)-)BENZENE   WHEREIN R1 IS HYDROGEN OR LOER ALKYL HAVING FROM 1 TO ABOUT 4 CARBON ATOMS, R2 REPRESENTS   RX-N(-RY)-CO-   IN WHICH RX AND RY ARE INDEPENDENTLY HYDROGEN, ALKYL, ALLYL, LOWER ALKOXYL ALKYL, CYCLOHEXYL, 2-CHLOROALKYL, PHENYL, BENZYL, OR SUBSITUTTED-PHENYL IN WHICH THE SUBSTITUENTS ARE CHLORO, NITRO, LOWER ALKYL, LOWER ALKOXY OR CYANO.

United States Patent Office Patented Oct. 1, 1974 3,839,581 BROMOACETANILIDE CARBAMIC ACID ESTERS USEFUL AS BIOCIDES Don R. Baker, Pinole, and Rugene G. Teach, El Cerrito, Calif., assignors to Staulfer Chemical Company, New

York, N.Y.

No Drawing. Application Mar. 24, 1973, Ser. No. 127,774,

now Patent No. 3,781,442, which is a division of application Ser. No. 806,717, Mar. 12, 1969, now abandoned. Divided and this application Aug. 3, 1973, Ser.

Int. Cl. A611; 27/00 US. Cl. 424-300 6 Claims ABSTRACT OF THE DISCLOSURE Bromoacetanilides as new compositions and their activity as microbiocides. Representative compounds include 3' hydroxy bromoacetanilide, 3'-(N-methylcarbamoyloxy) bromoacetanilide, 3' (N-isopropylcarbamoyloxy) bromoacetanilide, 3-(N-allylcarbamoyloxy) bromoacetanilide and 4'-hydroxy bromoacetanilide.

wherein R is hydrogen or lower alkyl having from 1 to about 4 carbon atoms, inclusive, R represents (1) hydrogen;

tL N in which R and R are independently hydrogen, alkyl, allyl, lower ,alkoxyalkyl, cyclohexyl, 2-chloroallyl, phenyl, benzyl, or substituted-phenyl in which the substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano, R and R taken together represents an alkylene containing 4 to 6 carbon atoms, inclusive, or lower alkylsubstituted alkylene containing a total of to 8 carbon atoms, inclusive:

in which R is alkyl, phenyl, substituted-phenyl in which the substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano; I

0 R3 in which R is alkyl, phenyl, substituted-phenyl in which the substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano;

i -CRc in which R is hydrogen, alkyl, haloalkyl, phenyl, substituted phenyl in which the substituents are chloro, nitro, lower alkyl, lower alkoxy or cyano;

provided that when R is hydrogen and R is hydrogen then the group is in the meta-position. The above compounds as well as compounds in which R is hydrogen and R is hydrogen and is in the para-position, are effective microbiocides.

In the above description, the following preferred embodiments are intended for the various groups. Alkyl preferably includes, unless otherwise provided for, those members which contain from 1 to about 6 carbon atoms, inclusive, in both straight chain and branched chain configurations, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, amyl, isoamyl, n-hexyl, isohexyl, and the like; and lower alkoxyalkyl preferably includes those members which contain a total of not more than 6 carbon atoms, for example, methoxymethyl, methoxyethyl, ethoxyrnethyl, methoxypropyl, ethoxypropyl, propoxypropyl, ethoxybutyl, methoxyamyl, and the like. Haloalkyl preferably includes those alkyl members which contain from 1 to about 4 carbon atoms, inclusive, and are substituted with at least one halogen such as chlorine, bromine and iodine. Lower alkyl and lower alkoxy preferably include those members which contain from 1 to about 4 carbon atoms, inclusive, in either straight chain or branched chain configurations.

The compounds herein described can be prepared by one of several methods, depending upon the nature of the starting materials and products desired. The compound -hydroxybromoacetanilide within the scope of this invention can be conveniently prepared by the condensation of m-aminophenol and bromoacetyl bromide. This preparation is specifically described in Example I below. Starting with either the 3'- or 4-hydroxybromoacetanilide subsequent condensation reactions can be performed which will ultimately yield other members of this series. Generally, these reactions are performed in a suitable solvent, such as benzene, toluene, acetone, methylethyl ketone and the like. The monosubstituted carbamate condensation reactions are carried out employing the appropriate isocyanate in the presence of catalysts, such as triethylene diamine and dibutyltin dilaurate, in order to facilitate the completion of the reaction. Alternatively, the carbamate derivatives disclosed herein, preferably when R and R are both hydrogen, are prepared by conversion of the substituted-phenol to the corresponding chloroformate using phosgene, followed by reaction with the appropriate primary or secondary amine or ammonia. The preparation of the sulfonate, dialkyl carbamate, carbonate and carboxylate derivatives are prepared using the appropriate acid halide and an acid acceptor such as pyridine, triethylamine, sodium bicarbonate and the like. After the reaction is completed, the solvent is removed and the product recovered therefrom. Upon isolation of the crude product, final recovery of the purified material is accomplished by normal workup procedures, such as crystallization or distillation.

It has been found that the compounds as defined supra are effective bacteriostatic and fungistatic agents. Whereas microbiological growths on various substances cause deterioration by the presence of the infestation, the application of an agent to retard this adverse growth is desired. Such substances liable to fungus and bacterial infection include cloth, leather, paint, soaps, paper, wood, plastic, oil, and the like. It is contemplated herein that the microbiocidal compositions of the present invention may be effectively incorporated or applied to any of the substances susceptible to microbiological growths.

For maximum effectiveness, the active ingredients of the present invention are admixed in microbiostaticly effective amounts with an inert adjuvant. In order to provide formulations particularly adapted for ready and efiicient application to the materials to be treated, such formulations comprise those of both the liquid and solid types as well as the aerosol type formulations. Application can be directly to the substance to be protected from fungus and bacterial growth. In the pure state the active ingredient may be too effective or too potent in some applications to have practical utility. A convenient method of treating cloth is by formulating the active ingredient with a soap or detergent and thereby imparting antiseptic or microbiocidal properties to the cloth as it is washed therewith.

For most effective protection it is preferred to apply the materials in intimate contact but thoroughly dispersed on or nearly in the surface to be protected. Threfore, the active ingredients have incorporated therewith a relatively inert agent or adjuvant as a dispersing medium, utilizing methods well known to those skilled in the art.

Suitable formulations of the compounds of this invention comprise the above-defined active ingredients and a suitable material as an adjuvant therefore. Fungistat and bacteriostat compositions are advantageously formulated by first preparing a solution thereof in an organic solvent and then adding the resulting solution to water or other carrier. If necessary, an emulsifying agent may be employed. The compositions may also be incorporated into solid carriers such as clay, talc, pumice, soap, and the like. They may also be dissolved in liquefied gases such as fluorochloroethans or methyl chloride and applied from aerosol bombs containing the solution. It should be noted that suitable formulations may also include adhesive agents, indicators, and other microbiocidal ingredients. Other ingredients may be supplmentary insecticides, fungicides, bacteriocides, nematocides or selective herbicides.

Since the amount of active agent of the present invention which is employed will vary with the microbiocidal effect sought, the utility of the treated material, type and dimensions of the material treated, it is evident that no rigid limits can be set forth on the quantity required. Determination of the optimum effective concentration for a specific performance is readily ascertainable by routine procedures, as will be apparent to those skilled in the art.

Preparation of the compounds of the present invention are illustrated by the following particular examples. Followin the examples is a table of compounds which are prepared according to the procedures described herein.

4 EXAMPLE 1 Preparation of 3-Hydroxybromoacetanilide m-Aminophenol, 66.5 g. (0.61 moles), is dissolved in 500 ml. of a 50/50 (v/v) mixture of glacial acetic acid and saturated sodium acetate solution. The mixture is cooled to approximately 10 C. and 200 g. (0.99 moles) of bromoacetyl bromide is added dropwise. The temperature is maintained between 10 and 20 C. When addition is complete, the mixture is stirred while cooling until the temperature is about 5 C. The product is filtered off, Washed successively with cold water, saturated sodium bicarbonate solution and finally two portions of water. The product is dried under vacuum. The yield of the title compound is 121 g. (86 percent of theory) m.p. 167-170 C.

EXAMPLE II Preparation of 3-N-Methyl Carbamoyloxy Bromoacetanilide 3-Hydroxybromoacetanilide, 34.5 g. (0.15 moles) in 250 ml. of acetone containing approximately 100 mg. of triethylene diamine and 5 drops of dibutyltin dilaurate is refluxed for two hours with 9.4 g. (0.165 moles) of methyl isocyanate. On cooling, the product crystallizes from solution and is recovered by filtration. There is obtained 24 g. (56 percent of theory) of the title compound, m.p. 136 l38 C.

TABLE I C-CHzBI Compound 4 number R1 R Position M.P.,C.

1 H H- Meta 167-170 2 H C(OgNHCH; Meta" 136-138 3 H C(O NHCH(CH=)1 Meta 144-149 4; H C(O)NHOH;CH=CH;....- Meta 122-125 5 H C(O)NH(cyclohexyl) Meta 163-165 6 H H Para 141-144 Other examples of compounds falling within the generic formula presented herein, which are preparable by the aforedescribed procedures and which may be formulated into microbiocidal compositions and applied as herein illustrated, are:

Compound number Position Meta;

'I'ABLEContinued Compound number R; B, Position 02H. Same as above H S(O2 CHa.-.. H S(z) -C4 o C2 5 S(O2)C2Hs. H C(0)0 H Meta H Para 02 S (0)2phenyl Meta H S(0z) (p-Cl-phenyl).. Meta 02111 S (02) (m-Cl-phenyl) Para H S(Oz)(m-NOz-pl1enyl Meta H S(O 2) (CHs-phenyl)- Meta H S (0 2) (P-CHgO-phenyl) Meta i-Ca -r S(O2)(p-CN-pheny1) Meta H S(O2)(pBr-phenyl) Meta H C(O) O- henyl Meta l-Ca 1 C (0)0 gp-Cl-phenyl) Para H C (O; 0 (m-Noi-phenyl) Meta C I C (0 O (p-CHg-phenyl) Meta H C (0)0 (pCHsO-phenyl Meta CH: C (O) O (O-CHa-phenyl) Para 02H; 0 (0)0 (p-CN-phenyl). P m H C 0 H213 M CHI C(O)CH2CH2CI Meta H C (O)-p-Cl-phenyl Para CH: C(O;-m-NO1-phenyl Meta. 02 C (0 Para H C (O)-p-CH;0-phenyl Pa ra CH: C (O)-p-C N-phenyl. Meta H C(oyphenyl Meta 02H; C(O)-phen 1.... Meta. C2H5 Para H C (O) N Meta 'ot o O(O)NH(p-CN-phenyl Meta H (O)NH( CH o-phenyl) Para H C (O)NH (p-CHa-phenyl)..- Meta. CH: C (O) NH (o-CH -phenyb Meta.

As previously mentioned, the herein described compounds are microbiostatic agents which are useful and valuable in controlling fungi and bacteria. The compounds of this invention are tested as microbiocides in the following manner.

In Vitro Vial Tests The compounds are tested to determine the microbiostatic efficacy when in contact with growing fungi or bacteria in an artificial medium. For each candidate compound four l-ounce vials are partially filled, two with malt broth and two with nutrient broth. The compound to be tested is placed in the vials at the desired concentration (expressed in parts per million). The vials containing malt broth are inoculated with water suspensions of spores of the desired fungi, Aspergillus niger and Penicillium italicum, and cells of the bacteria, Escherichia coli and Staphylococcus aureus, are inoculated into the vials containing nutrient broth (one specie of organism per vial). The vials are then sealed and held for one week, after which time the growth of the organisms is observed and noted. The tests are repeated using lower concentrations of the candidate compounds to determine the lowest concentration that can be used and still oifer some control of the growth of the organism. Table II shows the results of the in Vitro tests.

TABLE II.IN VITRO TEST [Lowest efiective concentration (p.p.m.)]

NOTE.-( Indicates partial control at this concentration. A=Chlorolanalog of Compound number 1. B=Chlorolanalog of Compound number 3.

Soap Plug Test Samples of Compound Nos. 1 and 3, and 3,4,4-Trichlorocarb-anilide (TCC) are incorporated at a level of 1% in sodium stearate using acetone with the slurry. The products are air dried and pressed in a metal tube to form a soap plug approximately 10 mm. in diameter and 2 mm. thick. These are placed on nutrient agar plates that have been streaked separately with Escherichia coli and Staphylococcus aureus cells. The plates are incubated at 37 C. for 17 hours. The radius of the zone of biological inhibition around the soap plug is measured. The data from this test are as follows:

TABLE III.SOAP PLUG TEST Detergent Formulation Test Samples of Compound Nos. 1 and 3 of 10-20 mg. are dissolved in 5 ml. of acetone and added to weighed amounts of a commercial laundry detergent identified as Tide, a trademark owned by Procter and Gamble (a mixture of lauryl sulfate and alkyl benzenesulfonate with tripolyphosphate as a binder), to give a concentration of 0.2% in the detergent. From these detergent samples 1 g. is added to 500 ml. of 50 C. tap water. To this wash solution is added 25 g. of laundered white cotton duck and the mixture agitated by stirring for 10 minutes. The cloth samples are hand wrung and each sample twice rinsed with stirring for 10 minutes in 500 ml. of 50 C. tap water. Thereafter, the cloth samples are hand wrung and air dried. Samples (1" square approximately) of the treated cloth samples are placed on nutrient agar plates that have been separately streaked with Staphylococcus aureus, Escherichia coil, Brevibacterium ammoniagenes, and Trichophyton mentagrophytes.

The following controls are included in this test: a blank and a control containing a commercial laundry detergent identified as Dreft, a trademark owned by 'Procter and Gamble (active ingredients are sodium doder'yl-benzene sulfonate, sodium perborate), which contains the biocide 3,3,4-trichlorocarbanilide (TCC). The plates are incubated at 37 C. for various lengths of time to provide growth for the organisms at which time the zone of biological inhibition around the cloth samples is measured. The radius of the zone of biological inhibition around the cloth samples are reported in the following Table IV.

TABLE IV.DETERGENT FORMULATION TEST What is claimed is: 1. The method of controlling the growth of bacteria and fungi comprising applying thereto an effective amount of .a compound having the formula (R-CHQ B I.

7 8 wherein R is hydrogen or lower alkyl having from 1 t0 3. The method according to Claim 2 in which 'R is about 4 carbon atoms, R represents hydrogen and R is methyl.

4. The method according to Claim 2 in which R is hydrogen and R is isopropyl. *5. The method according to Claim 2 in which R is R, hydrogen and R is allyl.

6. The method according to Claim 2 in which R is in which R and B are independently hydrogen, alkyl, hydrogen and y 5 y l hexyl. allyl, lower alkoxyl alkyl, cyclohexyl, 2-chloroallyl, phenyl,

benzyl, or substituted-phenyl in which the substituents are 10 References Cited chloro, nitro, lower alkyl, lower alkoxy or cy-ano. UNITED S AT S PATENTS 2. The method according to Claim 1 in which R; is 3 714 219 1/1973 Baker et a1 hydwgm mulls 3,777,035 12/1973 Teach et a1. 424 300 E 1 3,777,036 12/1973 Nikles et al. 424-300 -N R! SAM ROSEN, Primary Examiner 

1. THE METHOD OF CONTROLLING THE GROWTH OF BACTERIA AND FUNGI COMPRISING APPLYING THEREOF AN EFFECTIVE AMOUNT OF A COMPOUND HAVING THE FORMULA 